TGF-β sensitivity restrains CD8+ T cell homeostatic proliferation by enforcing sensitivity to IL-7 and IL-15

• Published in: PloS one Vol. 7; no. 8; p. e42268
• Main Authors: Johnson, Lisa D S, Jameson, Stephen C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-08-2012; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Biology; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Computer memory; Cytokines; Genes, Dominant - genetics; Genotype & phenotype; Growth factors; Histocompatibility Antigens Class I - immunology; Homeostasis; Immune response; Immune system; Immunological memory; Immunology; Interleukin 15; Interleukin 7; Interleukin-15 - metabolism; Interleukin-7 - metabolism; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Lymphopenia; Lymphopenia - immunology; Lymphopenia - pathology; Major histocompatibility complex; Medicine; Memory cells; Mice; Phenotypes; Protein-Serine-Threonine Kinases - genetics; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta - genetics; Sensitivity; Sensitivity enhancement; Spleen; T cell receptors; Transforming Growth Factor beta - metabolism; United States > US; Minnesota
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042268

The pleiotropic cytokine TGF-β has been implicated in the regulation of numerous aspects of the immune response, including naïve T cell homeostasis. Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity. Here we show naïve DNRII CD8 T cells exhibit enhanced lymphopenia-driven proliferation and generation of "homeostatic" memory cells. However, this enhanced response occurred in the absence of IL-15 and, unexpectedly, even in the combined absence of IL-7 and IL-15, which were thought essential for CD8 T cell homeostatic expansion. DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues. These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).